This invention pertains to an improved process for the preparation of uniform, spherical beads of up to 5 mm diameter of a crosslinked, water-insoluble hydrogel by suspension polymerization in a concentrated aqueous salt solution of 95-30% by weight of a monoolefinic monomer containing at least 5% of a hydroxy substituted hydrophilic vinyl monomer with 5-70% by weight of a terminal polyolefinic macromer crosslinking agent in the presence of water-insoluble, gelatinous, strong water-bonding inorganic metal hydroxides as suspending agents in the absence of excess alkali. The hydrogels have a host of pharmaceutical and industrial uses. The spherical beads exhibit a degree of swelling in water of from 5 to 200%.
Hydrogels have been described since 1956 (U.S. Pat. No. 2,976,576) and subsequently a large number of patents have been issued describing the synthesis and use of hydrogels based primarily on 2-hydroxyethyl methacrylate and, to a lesser extent, on N-vinylpyrrolidone. Typically, these hydrogels are crosslinked, water-swellable polymers made by copolymerization of 2-hydroxyethyl methacrylate with a small amount of ethylene or butylene dimethacrylate. They are used as polymeric, inert carriers for active substances, which are slowly and controllably released from these carriers; such active substances may be drugs (U.S. Pat. Nos. 3,574,826; 3,577,512; 3,551,556; 3,520,949; 3,576,760; 3,641,237; 3,660,563); agricultural chemicals (U.S. Pat. No. 3,576,760); or fragrances (U.S. Pat. Nos. 3,567,118; 3,697,643).
Their uses as antifogging coatings (U.S. Pat. No. 3,488,215), body implants and bandages have also been described in U.S. Pat. Nos. 3,577,516; 3,695,921, 3,512,183; 3,674,901. The widely used soft contact lens consists of this material (U.S. Pat. Nos. 3,488,111; 3,660,545).
In the pharmaceutical field the main interest lies in the slow and controllable release of drugs from such hydrogels. Drug-containing hydrogel preparations have been described as being in the form of bandages; subcutaneous implants; buccal devices, intrauterine devices, eye inserts. They are made by complicated fabrication procedures which usually involves casting the monomer solution into a suitable mold and polymerizing in the presence of a free radical generating initiator.
The use of drug loaded hydrogel granules as an oral dose form has also been suggested (U.S. Pat. No. 3,551,556). It is indeed one of the most useful applications of this concept in medicine since it allows the delivery into the bloodstream of an orally taken drug to be spread out over several hours in a reproducible manner. This eliminates wasteful and potentially dangerous peak drug concentrations in the blood, while prolonging the time during which preferred and effective drug levels in the blood are maintained.
There are two methods, by which hydrogel granules can be prepared. (1) One method consists of dicing or granulating a hydrogel sheet cast in the conventional manner and screening out the proper particle size. This method has several disadvantages: (a) It involves time consuming bulk polymerization of large amounts of materials in the form of relatively thin sheets; (b) the final product consists of jagged, rough particles with large surface area and sharp edges which are not only objectional from the aesthetic standpoint, but also are ill-suited for the controlled release of a drug, which depends on a uniform diffusion rate and therefore on uniform particles with well-defined surface and volume.
(2) The second method of making hydrogel granules, and by far the superior one, is suspension polymerization. Suspension polymerization consists of suspending a liquid monomer phase in a nonsolvent medium by stirring and with the aid of a protective colloid as a stabilizer, and polymerizing the stirred suspension by conventional means. Polymerization is heat induced or catalyzed by decomposition of a free radical chemical initiator. This method yield uniformly spherical beads in a one-step process and is widely used in the production of polystyrene, poly(vinyl chloride) and polyacryaltes, and poly(vinyl acetate). A good summary of the present state of the art is given by E. Farber in the Encyclopedia of Polymer Science and Technology, Vol. 13, pp 552-571, (1970), Interscience, N.Y. The relevant teachings therein are incorporated herein by reference. In case of water-soluble monomers used in the production of hydrogels, such as 2-hydroxyethyl methacrylate and N-vinylpyrrolidone, the nonsolvent medium is usually an organic liquid or an aqueous salt solution.
In U.S. Pat. No. 3,390,050 suspension polymerization of water-soluble monomers in the presence of large amounts of active ingredients is described. This process is, however, not suitable for the preparation of hydrogel beads for an orally administered drug since it is impossible to purify the polymer without leaching out the drug.
Most references to suspension polymerization of a 2-hydroxyethyl methacrylate refer to silicone oil or organic media such as mineral oil or xylene as the insoluble suspending phase (U.S. Pat. Nos. 3,567,118; 3,574,826; 3,575,123; 3,577,518; 3,583,957). These processes give generally particles with very irregular, imperfect and porous surfaces, unsuited for uses where diffusion rather than adsorption and desorption is the working mechanism. Besides these factors, the workup of the polymer on a technical scale would pose a problem.
Suspension polymerization of 2-hydroxyethyl methacrylate (HEMA) in the presence of 0.5 to 2% of shortchain cross-linking agents (a composition conventionally named "Hydron") and using an aqueous salt solution as medium has been described in U.S. Pat. No. 3,689,634, but there is no mention of a suspending agent as being a necessary ingredient of the recipe. However, it can be demonstrated that without such a suspending agent no useful particles or beads are obtained, only large agglomerations of polymer.
It is, however, well-known in the prior art that certain water-soluble polymers, such as polyvinylpyrrolidone and hydroxyethyl cellulose are excellent suspending agents for suspension polymerization. It is also known that certain highly insoluble inorganic compounds such as calcium sulfate, barium sulfate, calcium phosphate, magnesium phosphate, calcium carbonate and magnesium hydroxide are also useful.
The use of magnesium hydroxide as the suspension stabilizer in the suspension polymerization of vinyl monomers is disclosed in U.S. Pat. No. 2,801,992, but with the explicit teaching that excess alkali or free hydroxyl ions must be present. The magnesium hydroxide in the absence of excess alkali is ineffective as a suspension stabilizer. Indeed, even a stoichiometric amount of alkali to form magnesium hydroxide is insufficient to produce an effective stabilizer.
While the presence of excess alkali and free hydroxyl ions (high pH values) would cause no deleterious side effects with some suspension polymerization systems, there are many vinyl monomers, such as the acrylic esters, vinyl acetate and the like, which could undergo undesired base catalyzed hydrolysis in such systems at high pH values. It is certainly preferred to polymerize such vinyl monomers under essentially neutral conditions not within the purview of the teachings of U.S. Pat. No. 2,801,992.
It was found when water-soluble polymers were used as suspending agents that the hydrogel granules were of irregular shape and with very porous surfaces. If uniform beads were formed, they were of such small size (e.g., &lt;0.3 mm diameter) as to be of no practical value for the slow release of active ingredients. The same was true for the inorganic suspending agents, except that even more agglomeration occurred. Of all inorganic compounds only the insoluble gelatinous metal hydroxides gave smooth beads. In the case of poly(2-hydroxyethyl methacrylate) or "Hydron" these beads were of unusable small sizes and not uniformly spherical. But in the presence of macromeric crosslinking agents as described in this invention, regular, uniformly smooth spherical beads of up to 5 mm diameter could be obtained.
In the course of these investigations it was now unexpectedly discovered that it is the simultaneous presence of at least 5% by weight of 2-hydroxyethyl methacrylate (HEMA) or another hydroxy substituted vinyl monomer and at least 5% by weight of a polyolefinic macromeric crosslinking agent in the polymerizing mixture, and insoluble gelatinous metal hydroxides in the absence of excess alkali or free hydroxyl ions in the suspending aqueous medium which allows the manufacture of uniform sperical beads with up to 5 mm diameter. The suspending medium is an aqueous salt solution dissolving HEMA to not over 10%. The particle size is easily controlled by stirring, slow stirring speeds resulting in large beads and higher speeds in small beads.
Although the instant process can be modified to make small beads (&lt;0.3 mm) by high speed stirring, no other known process is known to make uniform beads of over 0.3 mm other than the present invention. The preferred bead size for the controlled delivery of oral medications is from 0.6 mm to about 1.5 mm.
Some of the hydrogel compositions of this invention are the subject of U.S. Pat. No. 4,192,827.